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EP1326585B2 - Procede de preparation de formulations pulverulentes - Google Patents
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EP1326585B2 - Procede de preparation de formulations pulverulentes - Google Patents

Procede de preparation de formulations pulverulentes Download PDF

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Publication number
EP1326585B2
EP1326585B2 EP01986599A EP01986599A EP1326585B2 EP 1326585 B2 EP1326585 B2 EP 1326585B2 EP 01986599 A EP01986599 A EP 01986599A EP 01986599 A EP01986599 A EP 01986599A EP 1326585 B2 EP1326585 B2 EP 1326585B2
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EP
European Patent Office
Prior art keywords
excipient
particle size
process according
active ingredient
substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP01986599A
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German (de)
English (en)
Other versions
EP1326585B1 (fr
EP1326585A2 (fr
Inventor
Georg Böck
Michael Walz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Priority claimed from DE2001138022 external-priority patent/DE10138022A1/de
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to SI200130509T priority Critical patent/SI1326585T2/sl
Publication of EP1326585A2 publication Critical patent/EP1326585A2/fr
Publication of EP1326585B1 publication Critical patent/EP1326585B1/fr
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Publication of EP1326585B2 publication Critical patent/EP1326585B2/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to a novel process for the preparation of powdered preparations for inhalation.
  • the inhaled application of the active ingredient is suitable.
  • the application of active ingredient-containing inhalation powders is of particular importance.
  • the object mentioned at the outset is achieved by a process in which the substance having the smaller particle size distribution is applied to the substance having the coarser particle size distribution by means of a layer mixing process.
  • the inventive method for the preparation of inhalable powders is characterized in that N + m approximately equal portions of the substance with larger particle size distribution and N equal-sized portions of the substance with smaller particle size distribution are alternately layered in a suitable mixing vessel and after complete addition of the 2N + m layers of two components are mixed by means of a suitable mixer, wherein first the addition of a portion of the substance with a larger particle size, wherein N is an integer> 5 and wherein m is 0 or 1 means.
  • N is naturally dependent inter alia on the total amount of the powder mixture to be prepared. In the production of smaller batches, even with a smaller N, the desired effect of high homogeneity in terms of content uniformity can be achieved. In principle, it is preferred according to the invention if N is at least 10 or more, particularly preferably 20 or more, furthermore preferably 30 or more. The greater the N, and associated therewith, the greater the total number of layers of powder fractions formed, the more homogeneous in terms of content uniformity becomes the powder mixture.
  • the substance with the smaller particle size distribution which is very finely ground and present in a very low mass fraction in the resulting powder formulation, represents the active ingredient.
  • the substance having the larger particle size distribution which is coarsely ground and in a large mass fraction in the resulting powder formulation, the excipient.
  • the present invention relates in particular to a process for the preparation of inhalable powders containing less than 5%, preferably less than 2%, more preferably less than 1% active ingredient in admixture with a physiologically acceptable excipient.
  • preference is given to a process for the preparation of inhalable powders in which 0.04 to 0.8%, more preferably 0.08 to 0.64%, particularly preferably 0.16 to 0.4% of active ingredient in admixture with a physiologically acceptable excipient are included.
  • the active ingredient used according to the invention preferably has an average particle size of 0.5 to 10 .mu.m, preferably from 1 to 6 .mu.m, particularly preferably from 2 to 5 .mu.m.
  • the excipient which can be used in the process according to the invention preferably has an average particle size of from 10 to 100 .mu.m, preferably from 15 to 80 .mu.m, particularly preferably from 17 to 50 .mu.m.
  • Particularly preferred according to the invention are processes for the preparation of inhalable powders in which the excipient has an average particle size of 20-30 ⁇ m.
  • the two components are preferably added via a sieve granulator with a mesh size of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
  • the first portion of the N + m portions of the excipient is presented and then introduced the first portion of the N portions of the active ingredient in the mixing container.
  • the addition of the individual components usually takes place in approximately equal portions, it may be advantageous if the first of the N + m portions of excipient which is introduced into the mixing apparatus, a larger volume than the following portions of excipient ,
  • the addition of the two components via a sieve unit takes place alternately and in layers in more than 20, preferably more than 25, particularly preferably more than 30 layers.
  • the excipient may also consist of a mixture of coarser excipient with an average particle size of 15 to 80 microns and finer excipient with an average particle size of 1 to 9 microns, wherein the proportion of finer excipient in the total amount of adjuvant can be 1 to 20%.
  • the preparation of such inhalable powders is preferred according to the invention, in which the coarser excipient has an average particle size of from 17 to 50 ⁇ m, more preferably from 20 to 30 ⁇ m, and the finer excipient has an average particle size of 2 to 8 microns, more preferably from 3 to 7 microns.
  • average particle size refers to the 50% value from the volume distribution measured by a laser diffractometer according to the dry dispersion method.
  • an adjuvant mixture of coarser and finer excipient fractions such processes are preferred according to the invention with which inhalable powders are obtained in which the proportion of finer excipient in the total quantity of adjuvant is 3 to 15%, particularly preferably 5 to 10%.
  • the excipient mixture can be obtained using the method according to the invention as follows.
  • the two components are preferably added via a sieve granulator with a mesh size of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
  • the first fraction of the N + m portions of the coarser excipient is introduced and then introduced the first portion of the N portions of the finer excipient fraction in the mixing vessel.
  • the addition of the two components takes place alternately by layerwise sieving of the two components.
  • the preparation of the inhalation powder is carried out using the method according to the invention.
  • the two components are preferably added via a sieve granulator with a mesh size of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
  • the first portion of the N + m portions of the excipient mixture is preferably initially introduced, and then the first portion of the N portions of the active ingredient is introduced into the mixing container.
  • the addition of the two components via a sieve unit takes place alternately and in layers in more than 20, preferably more than 25, more preferably more than 30 layers.
  • the inhalable powders obtainable by means of the preparation process according to the invention may generally contain all active ingredients whose administration appears sensible on the inhalative route from a therapeutic point of view. Preference is given here to those active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids and dopamine agonists.
  • the betamimetics used here are preferably compounds selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, toluubuterol, mabuterol, 4 -Hydroxy-7- [2 - ⁇ [2 - ⁇ [3- (2-phenylethoxy) propyl] sulfonyl ⁇ ethyl] amino ⁇ ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl ) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl
  • betamimetics those active substances which are selected from the group consisting of fenoterol, - formoterol, salmeterol, mabuterol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4- N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4 -methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4 -me
  • the compounds formoterol and salmeterol are optionally of particular importance in the form of their racemates, their enantiomers, their diastereomers and optionally their pharmacologically acceptable acid addition salts and hydrates.
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate.
  • Particularly preferred are the salts in the case of salmeterol selected from hydrochloride, sulfate and xinafoate, of which the sulfates and xinafoates are particularly preferred.
  • Salmeterol x 1 ⁇ 2H 2 SO 4 and salmeterol xinafoate are of outstanding importance in accordance with the invention. Particularly preferred are the salts in the case of the formoterol selected from hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred. Of paramount importance to the invention is formoterol fumarate.
  • Salts which are selected from the group consisting of tiotropium salts, oxitropium salts and ipratropium salts are preferably used as anticholinergics in the processes according to the invention; tiotropium and ipratropium salts are particularly preferred.
  • the cations tiotropium, oxitropium and ipratropium are the pharmacologically active constituents.
  • the salts which can be used in the context of the present invention are the compounds which, in addition to tiotropium, oxitropium or ipratropium, as the counterion (anion) chloride, bromide, Containing iodide, sulfate, methanesulfonate or para-toluenesulfonate.
  • the methanesulfonate, chloride, bromide or iodide are preferred, the methanesulfonate or the bromide being of particular importance.
  • the anticholinergics selected from the group consisting of tiotropium bromide, oxitropium bromide and ipratropium bromide. Particularly preferred is the tiotropium bromide.
  • the aforementioned anticholinergics may optionally be in the form of their solvates or hydrates. In the case of tiotropium bromide, for example, tiotropium bromide monohydrate has particular importance according to the invention.
  • corticosteroids are understood as meaning compounds selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides, rofleponides, GW 215864, KSR 592, ST-126 and dexametasone.
  • the corticosteroids are preferably selected from the group consisting of flunisolides, beclomethasone, triamcinolones, budesonide, fluticasone, mometasone, ciclesonide and dexametasone, in which case the budesonide, Fluticasone, mometasone and ciclesonide, especially the budesonide and the fluticasone a special meaning.
  • corticosteroids instead of the term corticosteroids only the term steroids is used.
  • Reference to steroids in the context of the present invention includes reference to salts or derivatives that may be formed by the steroids.
  • Examples of possible salts or derivatives are: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • the corticosteroids may also be in the form of their hydrates.
  • dopamine agonists are understood as meaning compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan.
  • dopamine agonists are preferably used which are selected from the group consisting of pramipexole, talipexole and viozan, with pramipexole being of particular importance.
  • a reference to the above-mentioned dopamine agonists in the context of the present invention includes a reference to their possibly existing pharmacologically acceptable acid addition salts and optionally their hydrates.
  • physiologically acceptable acid addition salts which can be formed from the aforementioned dopamine agonists are, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric and maleic acid.
  • the inventive method for the preparation of powder mixtures for inhalation can be used for the preparation of inhalable powders containing one or more of the aforementioned active ingredients. If, for example, inhalation powders are to be prepared whose pharmaceutically active constituents consist of two different active substances, this can be ensured by means of the method according to the invention, for example, the N + m approximately equal portions of excipient or excipient mixture with about equal portions of the one active ingredient and P approximately the same size portions of the other active ingredient components are layered alternately into the mixing apparatus.
  • the process according to the invention is to be used for the production of inhalable powders which contain, for example, two active ingredients
  • the possible combinations of agents mentioned herein are, for example, one of the abovementioned anticholinergics with one of the abovementioned corticosteroids or one of the abovementioned anticholinergics with one of the abovementioned called betamimetics mentioned as preferred.
  • auxiliaries which can be used in the production process according to the invention include monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg dextranes), polyalcohols (eg sorbitol , Mannitol, xylitol), salts (eg sodium chloride, calciulecarbonate) or mixtures of these auxiliaries with one another.
  • mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred.
  • Lactose most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
  • the inhalation powders which can be obtained according to the preparation process according to the invention are distinguished by an extraordinarily high degree of homogeneity in terms of content uniformity. This lies in a range of ⁇ 8%, preferably ⁇ 6%, particularly preferably ⁇ 4%.
  • the inhalable powders which can be prepared by means of the method according to the invention optionally have even homogeneities in the sense of the single-dose accuracy, which is ⁇ 3%, optionally ⁇ 2%.
  • the inhalable powders obtainable by means of the method according to the invention can be administered, for example, by means of inhalers which deliver a single dose from a supply by means of a measuring chamber (eg according to FIG US 4570630A ) or other apparatus (eg according to DE 36 25 685 A ).
  • a measuring chamber eg according to FIG US 4570630A
  • other apparatus eg according to DE 36 25 685 A
  • the inhalable powders obtainable by means of the method according to the invention are filled into capsules (known as inhalers) which are used in inhalers such as in the WO 94/28958 described, apply.
  • the inhalable powder obtainable by means of the process according to the invention is to be filled into capsules (inhalettes) in the sense of the preferred application mentioned above, fillages of from 3 to 10 mg, preferably from 4 to 6 mg of inhalable powder per capsule are recommended, this filling quantity being largely dependent on The choice of the active ingredient used may be dependent.
  • the capsules contain between 1.2 and 80 ⁇ g of tiotropium cation in the above-mentioned quantities.
  • tiotropium bromide-preferred filling quantity of 4 to 6 mg of inhalable powder per capsule between 1.6 and 48 ⁇ g, preferably between 3.2 and 38.4 ⁇ g, more preferably between 6.4 and 24 ⁇ g of tiotropium are contained per capsule.
  • a content of, for example, 18 ⁇ g tiotropium corresponds to a content of about 21.7 ⁇ g tiotropium bromide.
  • capsules with a content of from 3 to 10 mg of inhalable powder preferably contain between 1.4 and 96.3 ⁇ g of tiotropium bromide.
  • At a preferred level of 4 to 6 mg of inhalable powder per Capsule contain between 1.9 and 57.8 ⁇ g, preferably between 3.9 and 46.2 ⁇ g, more preferably between 7.7 and 28.9 ⁇ g tiotropium bromide per capsule.
  • a content of, for example, 21.7 ⁇ g tiotropium bromide corresponds to a content of about 22.5 ⁇ g tiotropium bromide monohydrate.
  • capsules containing 3 to 10 mg of inhalable powder preferably contain between 1.5 and 100 ⁇ g of tiotropium bromide monohydrate.
  • capsules containing 3 to 10 mg of inhalable powder preferably contain between 1.5 and 100 ⁇ g of tiotropium bromide monohydrate.
  • a preferred filling quantity of 4 to 6 mg of inhalable powder per capsule between 2 and 60 ⁇ g, preferably between 4 and 48 ⁇ g, more preferably between 8 and 30 ⁇ g of tiotropium bromide monohydrate are contained per capsule.
  • lactose monohydrate (200M) is used as the coarser excipient. This can be obtained, for example, from the company DMV Intemational, 5460 Veghel / NL under the product name Pharmatose 200M.
  • lactose monohydrate (5 ⁇ ) is used as a finer excipient. This can be obtained by conventional processes (micronization) from lactose monohydrate 200M. Lactose monohydrate 200M may for example be obtained from DMV International, 5460 Veghel / NL under the product name Pharmatose 200M.
  • a suitable reaction vessel In a suitable reaction vessel are in 25.7 kg of water 15.0 kg of tiotropium bromide, which as described in the EP 418 716 A1 disclosed, can be produced registered.
  • the mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed.
  • Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the tiotropium bromide-containing solution and rinsed with 4.3 kg of water.
  • the resulting mixture is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter in a pre-heated to 70 ° C jacket temperature apparatus.
  • the filter is rinsed with 8.6 kg of water.
  • the contents of the apparatus are cooled at 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is further cooled to 10-15 ° C and the crystallization is completed by at least one hour stirring.
  • the crystals are isolated on a Nutschentrockner, washed the isolated crystal slurry with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals are dried at 25 ° C for 2 hours in a stream of nitrogen. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)
  • the crystalline tiotropium bromide monohydrate thus obtained is micronised by known methods to provide the active ingredient in the form of the average particle size corresponding to the specifications of the invention.
  • the average particle size is understood to be the value in ⁇ m at which 50% of the particles from the volume distribution have a smaller or the same particle size in comparison to the stated value.
  • laser diffraction / dry dispersion is used as the measurement method.
  • the devices are operated in accordance with the manufacturer's operating instructions.
  • instrument HELOS Laser Diffraction Spectrometer, (SympaTec) dispersing unit: RODOS dry disperser with suction funnel, (SympaTec) Sample volume: from 100 mg Product Feed: Vibrating trough Vibri, Fa. Sympatec Frequency d. Vibrating channel: 40 to 100% increasing Duration of sample supply: 1 to 15 sec.
  • the test substance is weighed on a map sheet. With another map sheet, all larger agglomerates are crushed. The powder is then spread on the front half of the vibrating trough (from about 1 cm from the front edge) dispersed. After starting the measurement, the frequency of the vibrating trough is varied from approx. 40% to 100% (towards the end of the measurement). The supply of the sample should be as continuous as possible. The amount of product must not be too large so that adequate dispersion is achieved. The time in which the entire sample is supplied is for 200 mg z. B. about 15 to 25 sec.
  • the test substance Approximately 500 mg of the test substance are weighed on a map sheet. With another map sheet, all larger agglomerates are crushed. The powder is transferred to the funnel of the vibrating trough. There is a clearance of 1.2 to 1.4 mm between the vibrating trough and the hopper. After the start of the measurement, the amplitude setting of the vibrating trough is increased from 0 to 40% until a continuous product flow occurs. Thereafter, it is reduced to an amplitude of about 18%. Towards the end of the measurement, the amplitude is increased to 100%.
  • step 1.1 for the preparation of an adjuvant mixture may also be omitted depending on the choice of the active ingredient. If a powder mixture is sought, which in addition to the active ingredient only contains excipient of a uniform coarser particle size distribution, it is possible to proceed directly according to step 1.2.
  • lactose monohydrate for inhalation purposes 200M
  • a suitable mixing container on a suitable sieve granulator with a sieve with a mesh size of 0.5 mm.
  • lactose monohydrate for inhalation purposes 200M
  • lactose monohydrate for inhalation purposes 200M
  • lactose monohydrate (5 ⁇ m) are added in 31 and 30 layers (tolerance: ⁇ 6 layers).
  • the sieved components are then mixed with a free-fall mixer (mixing: 900 revolutions)
  • the active ingredient content is 0.4%.
  • a suitable sieve granulator with a sieve with a mesh size of 0.5 mm are placed in a suitable mixing container about 1.1 to 1.7 kg excipient mixture (1.1). Subsequently, alternating tiotropium bromide monohydrate in portions of about 0.003 kg and excipient mixture (1.1) in increments of 0.6 to 0.8 kg in layers sieved.
  • the additive mixture and the active ingredient are added in 46 or 45 layers (tolerance: ⁇ 9 layers).
  • the sieved components are then mixed in a free-fall mixer (mixing: 900 revolutions).
  • the final mixture is added twice through a sieve granulator and then mixed in each case (mixing: 900 revolutions).
  • inhalation capsules of the following composition are obtained: Tiotropium bromide monohydrate: 0.0225 mg Lactose monohydrate (200 M): 5.2025 mg Lactose monohydrate (5 ⁇ m): 0.2750 mg Hard gelatin capsule: 49.0 mg Total: 54.5 mg
  • the inhalation powder required to prepare the capsule was obtained in analogy to Example 1.
  • the inhalation powder required to prepare the capsule was obtained in analogy to Example 1.

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Claims (8)

  1. Procédé de préparation de poudres d'inhalation, caractérisé en ce que N+m portions, de taille à peu près égale, d'une substance à distribution de tailles de particules plus grande, représentant la substance auxiliaire, et N portions, de taille égale, d'une substance à distribution de tailles de particules plus petite, représentant le principe actif, sont introduites alternativement par couche dans un récipient de mélange approprié et, après addition complète, les 2N+m couches des deux composants sont mélangées à l'aide d'un mélangeur approprié, sachant qu'est effectuée d'abord l'addition d'une portion de la substance à taille de particule plus grosse, N étant un nombre entier >5 et m étant le nombre 0 ou 1.
  2. Procédé selon la revendication 1, caractérisé en ce que l'addition couche par couche des différentes fractions s'effectue par l'intermédiaire d'un dispositif de tamisage approprié.
  3. Procédé selon l'une des revendications 1 ou 2, caractérisé en ce que m est le nombre 1.
  4. Procédé selon l'une des revendications 1, 2 ou 3, caractérisé en ce qu'une poudre d'inhalation, contenant moins de 5%, de préférence moins de 2% de principe actif est obtenue.
  5. Procédé selon l'une des revendications 1 à 4, caractérisé en ce que le principe actif utilisé présente une taille de particule comprise dans la fourchette de 0,5 à 10 µm, de préférence de 1 à 6 µm.
  6. Procédé selon l'une des revendications 1 à 5, caractérisé en ce que la substance auxiliaire utilisée présente une taille de particule moyenne comprise dans la fourchette de 10 à 100 µm, de préférence de 15 à 80 µm.
  7. Procédé selon l'une des revendications 1 à 5, caractérisé en ce que la substance auxiliaire est composée d'un mélange de substance auxiliaire plus grossière, ayant une taille de particule moyenne comprise dans la fourchette de 15 à 80 µm, et d'une substance auxiliaire plus fine, ayant une taille de particule moyenne comprise dans la fourchette de 1 à 9 µm, la proportion de substance auxiliaire plus fine dans la quantité totale de substance auxiliaire étant comprise dans la fourchette de 1 à 20 %.
  8. Procédé selon l'une des revendications 1 à 7, caractérisé en ce qu'un ou plusieurs composés, sélectionnés dans le groupe constitué des bêta-mimétiques, anticholinergiques, corticostéroïdes et dopamine agonistes, sont contenus en tant que principe actif.
EP01986599A 2000-10-12 2001-10-09 Procede de preparation de formulations pulverulentes Expired - Lifetime EP1326585B2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI200130509T SI1326585T2 (sl) 2000-10-12 2001-10-09 Postopek za pripravo praškastih formulacij

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DE10050635 2000-10-12
DE10050635 2000-10-12
DE10138022 2001-08-10
DE2001138022 DE10138022A1 (de) 2001-08-10 2001-08-10 Verfahren zur Herstellung von Pulverformulierungen
PCT/EP2001/011636 WO2002030390A2 (fr) 2000-10-12 2001-10-09 Procede de preparation de formulations pulverulentes

Publications (3)

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EP1326585A2 EP1326585A2 (fr) 2003-07-16
EP1326585B1 EP1326585B1 (fr) 2006-03-08
EP1326585B2 true EP1326585B2 (fr) 2010-09-29

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ZA200301349B (en) 2004-06-30
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EA004689B1 (ru) 2004-06-24
EE200300170A (et) 2003-06-16
ME02762B (fr) 2011-05-10
US6585959B2 (en) 2003-07-01
ATE319422T1 (de) 2006-03-15
MXPA03003219A (es) 2004-12-03
DK1326585T4 (da) 2011-01-10
MY155912A (en) 2015-12-15
WO2002030390A2 (fr) 2002-04-18
EG24478A (en) 2009-08-03
KR20030051706A (ko) 2003-06-25
CA2425005A1 (fr) 2003-04-04
SI1326585T1 (sl) 2006-06-30
IL154919A0 (en) 2003-10-31
TWI283180B (en) 2007-07-01
HRP20030277B1 (en) 2011-09-30
KR100849837B1 (ko) 2008-08-01
EE05146B1 (et) 2009-04-15
MEP42708A (en) 2011-02-10
AU1822002A (en) 2002-04-22
NZ525781A (en) 2004-11-26
JP2009197025A (ja) 2009-09-03
UA75375C2 (en) 2006-04-17
JP4986369B2 (ja) 2012-07-25
RS50495B (sr) 2010-03-02
DE50109178D1 (de) 2006-05-04
YU27403A (sh) 2006-03-03
AR034166A1 (es) 2004-02-04
HU229512B1 (en) 2014-01-28
USRE38912E1 (en) 2005-12-06
SI1326585T2 (sl) 2011-01-31
BR0114316A (pt) 2003-08-26
JP2004510806A (ja) 2004-04-08
CA2425005C (fr) 2008-08-05
EP1326585B1 (fr) 2006-03-08
WO2002030390A3 (fr) 2002-06-27
AU2002218220B2 (en) 2006-06-15
CN1269470C (zh) 2006-08-16
NO333719B1 (no) 2013-09-02
CN1469733A (zh) 2004-01-21
PL204733B1 (pl) 2010-02-26
HUP0301268A3 (en) 2005-05-30
BG66194B1 (bg) 2012-01-31
EP1326585A2 (fr) 2003-07-16
EA200300429A1 (ru) 2003-10-30
PT1326585E (pt) 2006-05-31
HUP0301268A2 (hu) 2003-10-28
SK4372003A3 (en) 2003-07-01
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UY26960A1 (es) 2002-06-20
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NO20031692L (no) 2003-06-06
DK1326585T3 (da) 2006-05-22
PL362511A1 (en) 2004-11-02
US20020106332A1 (en) 2002-08-08
SA01220518B1 (ar) 2006-12-10

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